7CHV

Metallo-Beta-Lactamase VIM-2 in complex with 1-benzyl-1H-imidazole-2-carboxylic acid

7CHV の概要

• エントリーDOI: 10.2210/pdb7chv/pdb
• 分子名称: Beta-lactamase class B VIM-2, ZINC ION, 1-(phenylmethyl)imidazole-2-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: metallo-beta-lactamase vim-2, vim-2, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25169.92

構造登録者

Yan, Y.-H.,Li, G.-B. (登録日: 2020-07-06, 公開日: 2021-07-14, 最終更新日: 2023-11-29)

主引用文献

Dai, Q.,Yan, Y.,Ning, X.,Li, G.,Yu, J.,Deng, J.,Yang, L.,Li, G.B.
AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-beta-lactamases and indoleamine/tryptophan 2,3-dioxygenases.
Acta Pharm Sin B, 11:1931-1946, 2021

PubMed Abstract: We herein describe AncPhore, a versatile tool for drug discovery, which is characterized by pharmacophore feature analysis and anchor pharmacophore (, most important pharmacophore features) steered molecular fitting and virtual screening. Comparative analyses of numerous protein-ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important, commonly associated with protein conservative characteristics, and have significant contributions to the binding affinity. Performance evaluation of AncPhore showed that it had substantially improved prediction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features. To demonstrate the practicability of AncPhore, we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo--lactamases (MBLs); of them, and manifested potent inhibitory activity to VIM-2, NDM-1 and IMP-1 MBLs. Crystallographic analyses of VIM-2: complex revealed the precise inhibition mode of with VIM-2, highly consistent with the defined anchor pharmacophore features. Besides, we also identified new hit compounds by using AncPhore for indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), another class of clinically relevant metalloenzymes. This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.

PubMed: 34386329
DOI: 10.1016/j.apsb.2021.01.018

実験手法

X-RAY DIFFRACTION (2.174 Å)